New aspects of brain oxidative stress induced by tert-butylhydroperoxide.

Many diseases and aging may be associated with oxidative stress in the brain. However, the effects of oxidative stress in the brain should be more clearly described, especially in terms of effects on brain reduced glutathione (GSH). This issue was addressed by intracerebroventricular injection of a direct-acting oxidative stress inducing agent, tert-butylhydroperoxide. Oxidized glutathione (GSSG) levels in the brain increased by as much as 90-fold during tert-butylhydroperoxide-induced oxidative stress. At the same time, brain GSH levels decreased. The brain appears to retain GSSG and not reduce it or export it efficiently. Vitamin E levels in the striatum increased during tert-butylhydroperoxide-induced oxidative stress. Aging alters the ability of the brain to detoxify an oxidative stress, in that 8-month-old mice retain GSSG in their brains much more than 2-month-old mice. Eight-month-old mice were much more susceptible to tert-butylhydroperoxide-induced toxicity than 2-month-old mice. This may indicate that aging makes the brain more susceptible to oxidative damage.

Alzheimer's and Parkinson's disease. Brain levels of glutathione, glutathione disulfide, and vitamin E.

Human brain levels of glutathione (GSH), glutathione disulfide (GSSG), and vitamin E were measured in neurologically normal control patients and two groups of patients with neurodegeneration: those with Alzheimer's disease (AD), and AD with some features of Parkinson's disease (AD-PD). Control brain samples contained GSH levels more than 50 times higher than GSSG. The levels of GSH were highest in the caudate nucleus and lowest in the medulla. In patients with AD or AD-PD, hippocampal levels of GSH were significantly higher than controls. Patients with AD also demonstrated high GSH levels in the midbrain compared to normal. In contrast, patients with AD-PD did not have significantly elevated GSH levels in this site. GSSG levels were not significantly different in any brain region between controls and diseased patients. In control brains, the medulla had higher levels of vitamin E than any other brain region. The caudate nucleus had the lowest levels, which were about half the levels in the medulla. Control levels of vitamin E in the midbrain were about 18.8 micrograms/g. In AD patients the midbrain levels of vitamin E doubled to 42.3 micrograms/g. This doubling also occurred in AD-PD patients where midbrain vitamin E levels increased to 44.0 micrograms/g. These results may indicate that compensatory increases in GSH and vitamin E levels occur following damage to specific brain regions in patients with AD or AD-PD.

Oxygen free radicals and Parkinson's disease.

The involvement of oxygen radicals in the pathogenesis of Parkinson's disease has been suggested for some time. This article reviews the evidence supporting the involvement of oxygen radicals in the disease process in the brain. This includes a discussion of iron, lipid peroxidation, peroxidase, catalase, superoxide dismutase, and glutathione levels in the brain. In addition, various theories of induction of Parkinson's disease are discussed in relation to the possible involvement of oxygen radicals. These theories include the environmental toxin theory, the dopamine turnover theory, and the cerebral blood flow theory.

Effects of MPTP on the cerebrovasculature.

The neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, has been shown to cause pooling of blood in the brain microvasculature and decrease the permeability of the blood-brain barrier. All areas of the brain examined in this study were affected. This study points out the possibility that reduced nutrient uptake, hypoxia and ensuring free radical damage are involved in the mechanism of toxicity of this neurotoxin.

MPTP toxicity in the mouse brain and vitamin E.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) caused transient alterations in vitamin E levels in every brain region examined. However, vitamin E returned to normal levels within a few hours in all brain regions but the substantia nigra, where at 2 days vitamin E levels first rose above normal levels. Vitamin E deficient mice were much more susceptible to MPTP toxicity than controls, in terms of lethality and DOPAC depletion in the substantia nigra. However, in the same vitamin E deficient mice, the striatum was partially protected from neurotransmitter and metabolite depletion by MPTP. The mechanism of toxicity of MPTP may differ in the striatum and the midbrain.

Perturbations in cerebral oxygen radical formation and membrane order following vitamin E deficiency.

The effects of dietary vitamin E deficiency on mouse cerebral membrane order and oxygen reactive species were studied. Quantitation of vitamin E levels in several brain regions showed greatest deficiencies in striatum and cerebellum, followed by substantia nigra, and cortex. Vitamin E deficiency increased central-core membrane order in cerebral P2 fraction, but was without effect in the superficial hydrophilic membrane domain. Oxygen radical formation was studied using the probe 2',7'-dichlorofluorescein diacetate. Basal generation rates of oxygen reactive species were 2.5-fold higher when compared to control animals. While hepatic levels of vitamin E are much more reduced than brain levels, in deficient mice, the rate of oxygen radical formation in the liver was unaltered. This implies an special susceptibility of the brain to deficiency of this lipophilic antioxidant vitamin. Data demonstrate that endogenous levels of free radical scavengers, such as vitamin E, may play an important role in maintaining basal oxygen radical levels and membrane integrity. The dietary vitamin E depletion paradigm suggests that a relation exists between elevated levels of oxygen radicals and more rigid hydrophobic central-cores in cerebral membranes, effects that may play a role in mechanisms underlying the neuropathologic lesions observed following vitamin E deficiency.